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Near-total intestinal aganglionosis in the Waardenburg-Shah syndrome
Near-Total Intestinal Aganglionosis in the Waardenburg-Shah Syndrome By Walton
K.T.
Shim,
Marta
Derieg,
Berkley
Honolulu,
Both pigmentation and otic defects of Waardenburg Syndrome and Hirschsprung’s disease have a common origin in neural crest cells and were described in 1951 and 1887, respectively. The clinical manifestations of both in the same patient were described in 1981 in 12 infants so afflicted. The authors present such a case of long segment aganglionosis in a 15-day-old Marshallese girl with Waardenburg-Shah syndrome and discuss diagnosis, treatment, and prognosis.
A
LTHOUGH the association of short segment rectosigmoid Hirschsprung’s disease and Waardenburg syndrome’ is well recognized, the association of near-total aganglionosis with this syndrome has only recently been described. It is important for pediatric surgeons to recognize the association of pigmentary and otic defects with bowel dysfunction found in Hirschsprung’s disease. Also presented are a review of the basic molecular abnormalities now known to be operative in these disorders. Surgical treatment is possible, but technical difficulties are significant, and prognosis is still guarded. Our case raises difficult issues of cost-benefit considerations, where resources are limited. CASE
REPORT
The patient was the product of an uncomplicated, full-term pregnancy to a G2, P2 healthy mother, and father, both native to Majuro, Marshall Islands. She was discharged from the hospital on the first day of life. It was unknown when the first passage of meconium occurred, but she was readmitted 7 days later with fever and poor feeding, a distended abdomen, bilious vomiting. hyperextension of her extremities, and upward eye deviation suggesting seizures. Abdominal films showed dilated bowel with no colonic gas. She was treated with antibiotics and Phenobarbital, had multiple episodes of apnea with cyanosis, and was transferred to our facility at 15 days of age. On admission. she appeared alert, active, and in no distress. She was generally hypotonic with diminished subcutaneous tissue and skin hypopigmentation. She had sparse hair. a white forelock, white eyelashes, and eyebrows (Fig 1). There was mild hypertelorism, bluish-gray irides, a hypoplastic nodular right auricle, small tragus (Fig 2), and an absent right auditory canal. Her abdomen was moderately distended with normal bowel sounds. There were no masses or organomegaly. and there was a small amount of stool in her diaper. Abdominal films showed extensive bowel dilatation with no air noted in the rectum. Barium study showed a normal colonic caliber without transition zone. Rectal mucosal biopsy confirmed the absence of ganglion cells. On exploration, serial seromuscular biopsy results showed ganglion cells were absent beyond 10 cm of the Ligament of Trietz. In discussions with the neonatology staff and parents, we elected to pursue no further surgical therapy, and the patient returned to Majuro and was allowed to die. Journal
ofPediatric
Surgery,
Vol34,
No 12 (December),
1999: pp 1853-1855
R. Powell,
and
Y. Edward
Hsia
Hawaii
J Pediatr Saunders
Surg 34:1853-1855. Company.
INDEX WORDS: Waardenburg-Shah
Total
aganglionosis, syndrome.
Copyright
o
Hirschprung’s
1999
by
W.B.
disease,
DISCUSSION
Short segment rectosigmoid aganglionosis has been known to occur in patients with Waardenburg syndrome.213In 1981, Shah et al4 described in 5 families 12 infants with white forelock, eyebrows, and eyelashes, and almost total intestinal aganglionosis. A microcolon was found in those who underwent barium studies. Operative reports were available in only 8, and there was dilatation of the proximal ileum with collapse distally. Biopsy specimens were aganglionic, but biopsy sites and the extent of the aganglionic small bowel were not mentioned. All 12 patients died within 38 hours of “failure of ileostomy function.” The association of hair hypopigmentation, isochromia irides (light brown with a mosaic pigmentary pattern), and otic anomalies with total or almost total intestinal aganglionosis now bears the name of Waardenburg-Shah syndrome. The skin is generally unaffected, but our patient had generalized hypopigmentation. It is worth noting that patients with Waardenburg-Shah (Waardenburg, type IV) syndrome do not have telecanthus (broadened nasal root) seen in Waardenburg, type I, and usually not the congenital deafness associated with types I, II, and IIL5 Hypopigmentation, either a white forelock or changes in the eyebrows, and or isochromia irides, associated with bowel obstruction, should alert the pediatric surgeon to
From the Kapiolani Medical Center for Women and Children & the Depnrtments of Surgery, Pediatrics, and Genetics, John A. Bums School of Medicine, University of Hawaii, Honoiul~~, Hf. Supported in part by the Kapiolani Children’s Miracle Network Grant No. 298.29. Address reprint requests to Walton K.I: Shim, MD, 1319 Punahou St, Suite 1000, Honolulu, HI 96826. Copyright o 1999 by WB. Saunders Company 0022-3468/99/3412-0025$03.00/O 1853
SHIM
1854
ET AL
results in Hirschsprung’s disease on1y.l’ Paradoxically, heterozygous mutations in a different genetic locus, the SOX 20 gene, may result in the complete WaardenburgShah syndrome.12 Also, other gene loci not yet identified, have been mapped that may cause some or all of the Waardenburg syndrome spectrum. Thus, the complicated interaction of many genes associated with the various Waardenburg syndromes remains to be better elucidated. The surgical treatment of near-total intestinal aganglionosis is difficult at best, but becomes progressively more troublesome with increasing aganglionic length. Ziegler et all3 and Kimura et all4 have devised procedures to extend and enhance function, but with only 10 cm of jejunum, such procedures seemed impracticable, and transplantation seemed the only recourse available in our case. The semantics of Hirschsprung’s disease can become problematic. We suggest that more proximal aganglionosis, involving most or all of the small bowel, should be referred to as near-total or total aganglionosis rather than long segment disease. Finally, the cost-benefit ratio of any long-term care in the children with Waardenburg-Shah syndrome with
Fig 1. eyebrows.
Frontal
view
shows
the
white
forelock,
eyelashes,
and
the possibility of aganglionosis.6t7 A barium enema is frequently not diagnostic in young infants, necessitating a laparotomy for small bowel biopsies to identify the level of aganglionosis. Recently, molecular researchers have discovered important genes involved in embryological errors in this syndrome. Many of these genes produce proteins, called transcription factors, that regulate expression of other genes. Because these transcription factor genes are expressed in a variety of tissues at different embryological timing, errors may cause defects in seemingly unrelated organs. Mutations in 2 transcription factor genes, PAX3 and MZTF: are responsible for Waardenburg, types I-III and II, respectively.8 Both genes are expressed in melanocyte differentiation, but their role in cochlear development is less well understood. These 3 types of Waardenburg syndrome are inherited in an autosomal dominant pattern, ie, only 1 gene mutation (heterozygous) is necessary to disrupt the critical embryogenetic pathways. Waardenburg-Shah syndrome (type IV) usually is inherited as an autosomal recessive condition.9 Homozygous mutations in the endothelin-B ligand gene (EDN3) or its receptor gene (EDNBR) have been identified.“O Curiously, heterozygous mutations in either of these gene
Fig 2.
Hypoplastic,
nodular
right
auricle
and tragus.
NEAR-TOTAL
AGANGLIONOSIS
IN THE WAARDENBURG
SYNDROME
near-total aganglionosis and accompanying high morbidity and mortality needs to be carefully considered. In our case, although the decision to withhold treatment was difficult, the potential of exhausting the entire health
1855
budget of a developing country was an important consideration. Fortunately, our pediatric surgery and neonatology team was able to communicate effectively with the family and arrive at a mutually accepted decision.
REFERENCES 1. Waardenburg PJ: A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness. Am J HumGenet 3:195,1951 2. McKusick VA: Congenital deafness and Hirschsprung’s disease. N Engl J Med 288:691,1973 3. Omenn GS, McKusick VA: The association of Waardenburg syndrome and Hirschsprung megacolon. Am J Med Genet 3:217-23, 1979 4. Shah KN, DalaJ SJ, Desai MP, et al: White forelock, pigmentary disorder of irides, and long segment Hirschsprung disease: Possible variant of Waardenburg syndrome. 3 Pediau 99:432-435, 1981 5. Ambani LM: Waardenburg and Hirschspmng syndromes. .J Pediatr 102:802, 1983 6. Bonnet JP, Till M, Edery P, et al: Waardenburg-Hirschsprung disease in two sisters: A possible clue to the genetics of this association? Em J Pediatr Surg 6:245-248, 1996 7. Farndon PA, Bianchi A: Waardenbug’s syndrome associated with total aganglionosis. Arch Dis Child 58:932-933, 1983
8. Tassabehji M, Newton VE, Liu X2, et al: The mutational spectrum in Waardenburg syndrome. Hum Mol Genet 4:2131-2137,1995 9. Hofstra RM, Osinga J, Tan-Sindhunata G, et al: A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (ShahWaardenburg syndrome). Nat Genet 12:445-447,1996 10. Edery P, Attie T, Amiel J, et ai: Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nat Genet 12:442-444, 1996 11. Amiel J, Attie T, Jan D, et al: Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. Hum Mol Genet 5:355-337, 1996 12. Southard-Smith EM, Kos L, Pavan WJ: Sox 10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat Genet 18:60-64,1998 13. Ziegler MM, Ross AJ, Bishop HC: Total intestinal aganglionosis: A new technique for prolonged survival. J Pediatr Surg 22:82, 1987 14. Kimura K, Nishijima E, Muraji T, et al: Extensive aganglionosis: Further experience with the colonic patch graft procedure and long-term results. J Pediatr Surg 23:52, 1998
K.T.
Shim,
Marta
Derieg,
Berkley
Honolulu,
Both pigmentation and otic defects of Waardenburg Syndrome and Hirschsprung’s disease have a common origin in neural crest cells and were described in 1951 and 1887, respectively. The clinical manifestations of both in the same patient were described in 1981 in 12 infants so afflicted. The authors present such a case of long segment aganglionosis in a 15-day-old Marshallese girl with Waardenburg-Shah syndrome and discuss diagnosis, treatment, and prognosis.
A
LTHOUGH the association of short segment rectosigmoid Hirschsprung’s disease and Waardenburg syndrome’ is well recognized, the association of near-total aganglionosis with this syndrome has only recently been described. It is important for pediatric surgeons to recognize the association of pigmentary and otic defects with bowel dysfunction found in Hirschsprung’s disease. Also presented are a review of the basic molecular abnormalities now known to be operative in these disorders. Surgical treatment is possible, but technical difficulties are significant, and prognosis is still guarded. Our case raises difficult issues of cost-benefit considerations, where resources are limited. CASE
REPORT
The patient was the product of an uncomplicated, full-term pregnancy to a G2, P2 healthy mother, and father, both native to Majuro, Marshall Islands. She was discharged from the hospital on the first day of life. It was unknown when the first passage of meconium occurred, but she was readmitted 7 days later with fever and poor feeding, a distended abdomen, bilious vomiting. hyperextension of her extremities, and upward eye deviation suggesting seizures. Abdominal films showed dilated bowel with no colonic gas. She was treated with antibiotics and Phenobarbital, had multiple episodes of apnea with cyanosis, and was transferred to our facility at 15 days of age. On admission. she appeared alert, active, and in no distress. She was generally hypotonic with diminished subcutaneous tissue and skin hypopigmentation. She had sparse hair. a white forelock, white eyelashes, and eyebrows (Fig 1). There was mild hypertelorism, bluish-gray irides, a hypoplastic nodular right auricle, small tragus (Fig 2), and an absent right auditory canal. Her abdomen was moderately distended with normal bowel sounds. There were no masses or organomegaly. and there was a small amount of stool in her diaper. Abdominal films showed extensive bowel dilatation with no air noted in the rectum. Barium study showed a normal colonic caliber without transition zone. Rectal mucosal biopsy confirmed the absence of ganglion cells. On exploration, serial seromuscular biopsy results showed ganglion cells were absent beyond 10 cm of the Ligament of Trietz. In discussions with the neonatology staff and parents, we elected to pursue no further surgical therapy, and the patient returned to Majuro and was allowed to die. Journal
ofPediatric
Surgery,
Vol34,
No 12 (December),
1999: pp 1853-1855
R. Powell,
and
Y. Edward
Hsia
Hawaii
J Pediatr Saunders
Surg 34:1853-1855. Company.
INDEX WORDS: Waardenburg-Shah
Total
aganglionosis, syndrome.
Copyright
o
Hirschprung’s
1999
by
W.B.
disease,
DISCUSSION
Short segment rectosigmoid aganglionosis has been known to occur in patients with Waardenburg syndrome.213In 1981, Shah et al4 described in 5 families 12 infants with white forelock, eyebrows, and eyelashes, and almost total intestinal aganglionosis. A microcolon was found in those who underwent barium studies. Operative reports were available in only 8, and there was dilatation of the proximal ileum with collapse distally. Biopsy specimens were aganglionic, but biopsy sites and the extent of the aganglionic small bowel were not mentioned. All 12 patients died within 38 hours of “failure of ileostomy function.” The association of hair hypopigmentation, isochromia irides (light brown with a mosaic pigmentary pattern), and otic anomalies with total or almost total intestinal aganglionosis now bears the name of Waardenburg-Shah syndrome. The skin is generally unaffected, but our patient had generalized hypopigmentation. It is worth noting that patients with Waardenburg-Shah (Waardenburg, type IV) syndrome do not have telecanthus (broadened nasal root) seen in Waardenburg, type I, and usually not the congenital deafness associated with types I, II, and IIL5 Hypopigmentation, either a white forelock or changes in the eyebrows, and or isochromia irides, associated with bowel obstruction, should alert the pediatric surgeon to
From the Kapiolani Medical Center for Women and Children & the Depnrtments of Surgery, Pediatrics, and Genetics, John A. Bums School of Medicine, University of Hawaii, Honoiul~~, Hf. Supported in part by the Kapiolani Children’s Miracle Network Grant No. 298.29. Address reprint requests to Walton K.I: Shim, MD, 1319 Punahou St, Suite 1000, Honolulu, HI 96826. Copyright o 1999 by WB. Saunders Company 0022-3468/99/3412-0025$03.00/O 1853
SHIM
1854
ET AL
results in Hirschsprung’s disease on1y.l’ Paradoxically, heterozygous mutations in a different genetic locus, the SOX 20 gene, may result in the complete WaardenburgShah syndrome.12 Also, other gene loci not yet identified, have been mapped that may cause some or all of the Waardenburg syndrome spectrum. Thus, the complicated interaction of many genes associated with the various Waardenburg syndromes remains to be better elucidated. The surgical treatment of near-total intestinal aganglionosis is difficult at best, but becomes progressively more troublesome with increasing aganglionic length. Ziegler et all3 and Kimura et all4 have devised procedures to extend and enhance function, but with only 10 cm of jejunum, such procedures seemed impracticable, and transplantation seemed the only recourse available in our case. The semantics of Hirschsprung’s disease can become problematic. We suggest that more proximal aganglionosis, involving most or all of the small bowel, should be referred to as near-total or total aganglionosis rather than long segment disease. Finally, the cost-benefit ratio of any long-term care in the children with Waardenburg-Shah syndrome with
Fig 1. eyebrows.
Frontal
view
shows
the
white
forelock,
eyelashes,
and
the possibility of aganglionosis.6t7 A barium enema is frequently not diagnostic in young infants, necessitating a laparotomy for small bowel biopsies to identify the level of aganglionosis. Recently, molecular researchers have discovered important genes involved in embryological errors in this syndrome. Many of these genes produce proteins, called transcription factors, that regulate expression of other genes. Because these transcription factor genes are expressed in a variety of tissues at different embryological timing, errors may cause defects in seemingly unrelated organs. Mutations in 2 transcription factor genes, PAX3 and MZTF: are responsible for Waardenburg, types I-III and II, respectively.8 Both genes are expressed in melanocyte differentiation, but their role in cochlear development is less well understood. These 3 types of Waardenburg syndrome are inherited in an autosomal dominant pattern, ie, only 1 gene mutation (heterozygous) is necessary to disrupt the critical embryogenetic pathways. Waardenburg-Shah syndrome (type IV) usually is inherited as an autosomal recessive condition.9 Homozygous mutations in the endothelin-B ligand gene (EDN3) or its receptor gene (EDNBR) have been identified.“O Curiously, heterozygous mutations in either of these gene
Fig 2.
Hypoplastic,
nodular
right
auricle
and tragus.
NEAR-TOTAL
AGANGLIONOSIS
IN THE WAARDENBURG
SYNDROME
near-total aganglionosis and accompanying high morbidity and mortality needs to be carefully considered. In our case, although the decision to withhold treatment was difficult, the potential of exhausting the entire health
1855
budget of a developing country was an important consideration. Fortunately, our pediatric surgery and neonatology team was able to communicate effectively with the family and arrive at a mutually accepted decision.
REFERENCES 1. Waardenburg PJ: A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness. Am J HumGenet 3:195,1951 2. McKusick VA: Congenital deafness and Hirschsprung’s disease. N Engl J Med 288:691,1973 3. Omenn GS, McKusick VA: The association of Waardenburg syndrome and Hirschsprung megacolon. Am J Med Genet 3:217-23, 1979 4. Shah KN, DalaJ SJ, Desai MP, et al: White forelock, pigmentary disorder of irides, and long segment Hirschsprung disease: Possible variant of Waardenburg syndrome. 3 Pediau 99:432-435, 1981 5. Ambani LM: Waardenburg and Hirschspmng syndromes. .J Pediatr 102:802, 1983 6. Bonnet JP, Till M, Edery P, et al: Waardenburg-Hirschsprung disease in two sisters: A possible clue to the genetics of this association? Em J Pediatr Surg 6:245-248, 1996 7. Farndon PA, Bianchi A: Waardenbug’s syndrome associated with total aganglionosis. Arch Dis Child 58:932-933, 1983
8. Tassabehji M, Newton VE, Liu X2, et al: The mutational spectrum in Waardenburg syndrome. Hum Mol Genet 4:2131-2137,1995 9. Hofstra RM, Osinga J, Tan-Sindhunata G, et al: A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (ShahWaardenburg syndrome). Nat Genet 12:445-447,1996 10. Edery P, Attie T, Amiel J, et ai: Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nat Genet 12:442-444, 1996 11. Amiel J, Attie T, Jan D, et al: Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. Hum Mol Genet 5:355-337, 1996 12. Southard-Smith EM, Kos L, Pavan WJ: Sox 10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat Genet 18:60-64,1998 13. Ziegler MM, Ross AJ, Bishop HC: Total intestinal aganglionosis: A new technique for prolonged survival. J Pediatr Surg 22:82, 1987 14. Kimura K, Nishijima E, Muraji T, et al: Extensive aganglionosis: Further experience with the colonic patch graft procedure and long-term results. J Pediatr Surg 23:52, 1998